This invention relates to regimens of administering compounds which are antagonists of the progesterone receptor in combination with a progestin, an estrogen, or both.
Intracellular receptors (IR) form a class of structurally related gene regulators known as xe2x80x9cligand dependent transcription factorsxe2x80x9d (R. M. Evans, Science, 240, 889, 1988). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell""s DNA. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist. PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann, et al, Ann. N.Y. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/19997 A1, Jul. 4, 1996). PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al, Fertility and Sterility, 56, 402, 1991). PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5719136). PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).
Jones, et al, (U.S. Pat. No. 5,688,810) describe the PR antagonist dihydroquinoline 1. 
Jones, et al, described the enol ether 2 (U.S. Pat. No. 5,693,646) as a PR ligand. 
Jones, et al, described compound 3 (U.S. Pat. No. 5,696,127) as a PR ligand. 
Zhi, et al, described lactones 4, 5 and 6 as PR antagonists (J. Med. Chem, 41, 291, 1998). 
Zhi, et al, described the ether 7 as a PR antagonist (J. Med. Chem., 41, 291, 1998). 
Combs, et al., disclosed the amide 8 as a ligand for the PR (J. Med. Chem., 38, 4880, 1995). 
Perlman, et. al., described the vitamin D analog 9 as a PR ligand (Tet. Letters, 35, 2295, 1994). 
Hamann, et al, described the PR antagonist 10 (Ann. N.Y. Acad. Sci., 761, 383, 1995). 
Chen, et al, described the PR antagonist 11 (Chen, et al, POI-37, 16th Int. Cong. Het. Chem., Montana, 1997). 
Kurihari, et. al., described the PR ligand 12 (J. Antibiotics, 50, 360, 1997). 
The patent by Christ et al. (WO 9814436) claims cyclo amide such as compound A as inhibitors of HIV reverse transcriptase. Other prior art includes pyridazine cyclo amide such as compound B by Turck et al. (Tetrahedron, 49(3), 599-606(1993)) and compound such as C by Canonne et al. (J. heterocyclic Chem. 26, 113(1989)). No activity data were reported in Turek""s and Canonne"" publications. 
Regarding cyclic amides, Singh et al. and Kumar et al. (Singh et al. J. Med. Chem. 37(2), 248-254(1994); Kumar et al. J. Org. Chem. 57(25), 6995-6998(1992)) disclose compounds such as D and E claimed as cAMP PDE III inhibitors. 
U.S Pat. No. 5,521,166 (Grubb) teaches cyclophasic hormonal regimens comprising an antiprogestin and a progestin wherein the progestin is administered in the alternating presence and absence of an antiprogestin. The disclosed regimens also provide for use of an estrogen for a period of from 2-4 days to prevent breakthrough bleeding.
This invention provides combination therapies and dosing regimens utilizing antiprogestational agents in combination with one or more progestational agents. This invention further provides methods of treatment and dosing regimens further utilizing in combination with these antiprogestins and progestins, an estrogen, such as ethinyl estradiol.
These regimens and combinations may be administered to a mammal to induce contraception or for the treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate. Additional uses of the invention include stimulation of food intake. The uses herein for the treatment and/or prevention of the conditions or diseases described above includes the continuous administration or periodic discontinuation of administration of the invention to allow for minimization of effect dose or minimization of side effects or cyclic menstrual bleeding.
The use of this invention for contraception includes administration, preferably orally, to a female of child bearing age an antiprogestin in combination with an estrogen or progestin or both. These administration regimens are preferably carried out over 28 consecutive days, with a terminal portion of the cycle containing administration of no progestins, estrogens or anti-progestins.
The progestins of these combinations may be administered alone or in combination with an estrogen for the first 14-24 days of the cycle, the progestins being administered at a dosage range equal in progestational activity to about 35 xcexcg to about 150 xcexcg levonorgestrel per day, preferably equal in activity to from about 35 xcexcg to about 100 xcexcg levonorgestrel per day. An antiprogestin may then be administered alone or in combination with an estrogen for a period of 1 to 11 days to begin on any cycle day between day 14 and 24. The anti-progestin in these combinations may be administered at a dose of from about 2 xcexcg to about 50 xcexcg per day and the estrogen may be administered at a dose of from about 10 xcexcg to about 35 xcexcg per day. In an oral administration, a package or kit containing 28 tablets will include a placebo tablet on those days when the antiprogestin or progestin or estrogen is not administered.
In a preferred embodiment of this invention, the progestins of this invention may be administered alone or in combination with estrogen for the initial 18 to 21 days of a 28-day cycle, followed by administration of an antiprogestin, alone or in combination with an estrogen, for from 1 to 7 days.
The estrogen to be used in the combinations and formulations of this invention is preferably ethinyl estradiol.
Progestational agents useful with this invention include, but are not limited to, levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel, norethindrone, gestodene, norethindrone acetate, norgestimate, osaterone, cyproterone acetate, trimegestone, dienogest, drospirenone, nomegestrol, or (17-deacetyl)norgestimate. Among the preferred progestins for use in the combinations of this invention are levonorgestrel, gestodene and trimegestone.
Examples of orally administered regimens of this invention over a 28 day cycle include administration of a progestational agent solely for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 100 xcexcg of levonorgestrel. An antiprogestin compound of this invention may then be administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28. It is most preferred that the daily dosages of each relevant active ingredient be incorporated into a combined, single daily dosage unit, totaling 28 daily units per 28-day cycle.
In another regimen, a progestational agent may be coadministered for the first 21 days at a daily dose equal in progestational activity to from about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, with an estrogen, such as ethinyl estradiol, at a daily dose range of from about 10 to about 35 xcexcg. This may be followed as described above with an antiprogestin administered at a daily dose of from about 2 to 50 mg from day 22 to day 24, followed by no administration or administration of a placebo for days 25 to 28.
Still another regimen within the scope of this invention will include coadministration from days 1 to 21 of a progestational agent, the progestational agent, preferably levonorgestrel, being administered at a daily dose equal in progestational activity to from about 35 to about 100 xcexcg levonorgestrel, and an estrogen, such as ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg. This will be followed on days 22 to 24 by coadministration of an antiprogestin (2 to 50 mg/day) and an estrogen, such as ethinyl estradiol, at a daily dose of from about 10 to about 35 xcexcg. From day 25 to day 28, this regimen may be followed by no administration or administration of a placebo.
This invention also kits or packages of pharmaceutical formulations designed for use in the regimens described herein. These kits are preferably designed for daily oral administration over a 28-day cycle, preferably for one oral administration per day, and organized so as to indicate a single oral formulation or combination of oral formulations to be taken on each day of the 28-day cycle. Preferably each kit will include oral tablets to be taken on each the days specified, preferably one oral tablet will contain each of the combined daily dosages indicated.
According to the regimens described above, one 28-day kit may comprise:
a) an initial phase of from 14 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 xcexcg levonorgestrel;
b) a second phase of from 1 to 11 daily dosage units of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle in which no antiprogestin, progestin or estrogen is administered.
A preferred embodiment of this kit may comprise:
a) an initial phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in progestational activity to about 35 to about 100 xcexcg levonorgestrel;
b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin compound of this invention, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and
c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
Another 28-day cycle packaging regimen or kit of this invention comprises:
a) a first phase of from 18 to 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg; and
b) a second phase of from 1 to 7 daily dosage units of an antiprogestin of this invention at a daily dose of from about 2 to 50 mg; and
c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
A preferred embodiment of the kit described above may comprise:
a) a first phase of 21 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and, as an estrogen, ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg; and
b) a second phase of 3 daily dosage units for days 22 to 24 of an antiprogestin administered at a daily dose of from about 2 to 50 mg; and
c) optionally, a third phase of 4 daily dose units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
A further 28-day packaged regimen or kit of this invention comprises:
a) a first phase of from 18 to 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably equal in activity to from about 35 to about 100 xcexcg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg;
b) a second phase of from 1 to 7 daily dose units, each daily dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 xcexcg; and
c) optionally, an orally and pharmaceutically acceptable placebo for each of the remaining 0-9 days in the 28-day cycle in which no progestational agent, estrogen or antiprogestin is administered.
A preferred embodiment of the package or kit just described comprises:
a) a first phase of 21 daily dosage units, each containing a progestational agent of this invention at a daily dose equal in progestational activity to about 35 to about 150 xcexcg levonorgestrel, preferably from about 35 to about 100 xcexcg levonorgestrel, and ethinyl estradiol at a daily dose range of from about 10 to about 35 xcexcg;
b) a second phase of 3 daily dose units for days 22 to 24, each dose unit containing an antiprogestin of this invention at a concentration of from 2 to 50 mg; and ethinyl estradiol at a concentration of from about 10 to about 35 xcexcg; and
c) optionally, a third phase of 4 daily units of an orally and pharmaceutically acceptable placebo for each of days 25 to 28.
In each of the regimens and kits just described, it is preferred that the daily dosage of each pharmaceutically active component of the regimen remain fixed in each particular phase in which it is administered. It is also understood that the daily dose units described are to be administered in the order described, with the first phase followed in order by the second and third phases. To help facilitate compliance with each regimen, it is also preferred that the kits contain the placebo described for the final days of the cycle. It is further preferred that each package or kit comprise a pharmaceutically acceptable package having indicators for each day of the 28-day cycle, such as a labeled blister package or dial dispenser packages known in the art.
In this disclosure, the terms anti-progestational agents, anti-progestins and progesterone receptor antagonists are understood to be synonymous. Similarly, progestins, progestational agents and progesterone receptor agonists are understood to refer to compounds of the same activity.
These dosage regimens may be adjusted to provide the optimal therapeutic response. For example, several divided doses of each component may be administered daily or the dose may be proportionally increased or reduced as indicated by the exigencies of the therapeutic situation. In the descriptions herein, reference to a daily dosage unit may also include divided units which are administered over the course of each day of the cycle contemplated.
Compounds of this invention which may be used as the anti-progestational agents in the kits, methods and regimens herein are those of the Formula I: 
wherein:
A, B and D are N or CH, with the proviso that A, B and D can not all be CH;
R1 and R2 are independent substituents selected from H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, NRBCORA;
or R1 and R2 are fused to form a spirocyclic ring selected from a), b) or c), each spirocyclic ring optionally substituted by from 1 to 3 C1-C3 alkyl groups:
a) a 3 to 8 membered spirocyclic alkyl ring;
b) a 3 to 8 membered spirocyclic alkenyl ring; or
c) an optionally substituted 3 to 8 membered heterocyclic ring containing one to three heteroatoms from the group including O, S and N; the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from fluorine, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 thioalkyl, xe2x80x94CF3, xe2x80x94OH, xe2x80x94CN, NH2, xe2x80x94NH(C1 to C6 alkyl), or xe2x80x94N(C1 to C6 alkyl)2;
RA is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RB is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, or CORC;
RC is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
R4 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: 
X is taken from the group including halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, amino, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, CORD, OCORD, or NRECORD;
RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
Y and Z are independent substituents taken from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkoxy; or
R4 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR5 and containing one or two independent substituents from the group including H, halogen, CN, NO2 and C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORF, or NRGCORF;
RF is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RG is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R5 is H or C1 to C3 alkyl;
W is O or a chemical bond;
or a pharmaceutically acceptable salt thereof.
When W is a chemical bond, it is understood that Formula I exists as: 
Preferred antiprogestin compounds are those of the formula: 
wherein:
A, B and D are N or CH, with the proviso that A, B and D can not all be CH;
R1 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRBCORA;
R2 is H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRBCORA; or
R1 and R2 are fused to form the optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic rings described above;
RA is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RB is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C1 to C6 alkenyl, or CORC;
RC is H, C1 to C4 alkyl, substituted C1 to C4 alkyl, aryl, substituted aryl, C1 to C4 alkoxy, substituted C1 to C4 alkoxy, C1 to C4 aminoalkyl, or substituted C1 to C4 aminoalkyl;
R4 is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below: 
X is selected from halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, a 5 membered heterocyclic ring containing 1 to 3 heteroatoms, CORD, OCORD, or NRECORD;
RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
Y and Z are independent substituents selected from H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, or C1 to C3 thioalkoxy; or
R4 is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO2 or NR5 and containing one or two independent substituents from the group including H, halogen, CN, NO2 and C1 to C3 alkyl, or C1 to C3 alkoxy;
R5 is H or C1 to C3 alkyl;
W is O or a chemical bond;
or a pharmaceutically acceptable salt thereof.
Still, more preferred antiprogestin compounds are those of the formula: 
wherein:
A, B and D are N or CH, with the proviso that A, B and D cannot all be CH;
R1=R2 and are selected from the group of C1 to C3 alkyl, substituted C1 to C3 alkyl, or spirocyclic alkyl constructed by fusing R1 and R2 to form a 3 to 6 membered spirocyclic ring;
R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, or CORC;
RC is H, C1 to C4 alkyl, or C1 to C4 alkoxy;
R4 is a disubstituted benzene ring containing the substituents X, and Y as shown below: 
X is selected from the group of halogen, CN, C1 to C3 alkoxy, C1 to C3 alkyl, NO2, C1 to C3 perfluoroalkyl, 5 membered heterocyclic ring containing 1 to 3 heteroatoms, or C1 to C3 thioalkoxy;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position from the group including H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C4 alkyl, or C1 to C3 thioalkoxy; or
R4 is a five membered ring with the structure: 
U is O, S, or NR5;
R5 is H, or C1 to C3 alkyl, or C1 to C4 CO2alkyl;
Xxe2x80x2 is selected from halogen, CN, NO2, C1 to C3 alkyl, or C1 to C3 alkoxy;
Yxe2x80x2 is selected from H and C1 to C4 alkyl; or
R4 is a six membered ring with the structure: 
X1 is N or CX2;
X2 is halogen, CN or NO2;
or a pharmaceutically acceptable salt thereof.
Further preferred antiprogestational compounds include those of the formula: 
wherein:
A, B and D are N or CH, with the proviso that A, B and D can not all be CH;
R1=R2 and are selected from CH3 and spirocyclic alkyl constructed by fusing R1 and R2 to form a 6 membered spirocyclic ring;
R3 is H, OH, NH2, CH3, substituted methyl, or CORC;
RC is H, C1 to C3 alkyl, or C1 to C4 alkoxy;
R4 is a disubstituted benzene ring containing the substituents X and Y as shown below: 
X is halogen, CN, methoxy, NO2, or 2-thiazole;
Y is a substituent on the 4xe2x80x2 or 5xe2x80x2 position selected from H and F; or
R4 is a five membered ring of the structure: 
U is O, S, or NH;
Xxe2x80x2 is halogen, CN, or NO2;
Yxe2x80x2 is H or C1 to C4 alkyl;
W is O or a chemical bond;
or a pharmaceutically acceptable salt thereof.
The antiprogestin compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
The term xe2x80x9calkylxe2x80x9d is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups having one to eight carbon atoms, preferably one to six carbon atoms; xe2x80x9calkenylxe2x80x9d is intended to include both straight- and branched-chain alkyl groups with at least one carbon-carbon double bond and two to eight carbon atoms, preferably two to six carbon atoms; xe2x80x9calkynylxe2x80x9d group is intended to cover both straight- and branched-chain alkyl groups with at least one carbon-carbon triple bond and two to eight carbon atoms, preferably two to six carbon atoms.
The terms xe2x80x9csubstituted alkylxe2x80x9d, xe2x80x9csubstituted alkenylxe2x80x9d, and xe2x80x9csubstituted alkynylxe2x80x9d refer to alkyl, alkenyl, and alkynyl as just described having one or more substituents from the group including halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituents may be attached to any carbon of an alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable chemical moiety.
The term xe2x80x9carylxe2x80x9d is used herein to refer to an aromatic system which may be a single ring or multiple aromatic rings fused or linked together as such that at least one part of the fused or linked rings forms the conjugated aromatic system. The aryl groups include but not limited to phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl, phenanthryl.
The term xe2x80x9csubstituted arylxe2x80x9d refers to aryl as just defined having one to four substituents from the group including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.
The term xe2x80x9cheterocyclicxe2x80x9d is used herein to describe a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring which is saturated, partially unsaturated, or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group including N, O, and S atoms. The N and S atoms may be oxidized. The heterocyclic ring also includes any multicyclic ring in which any of above defined heterocyclic rings is fused to an aryl ring. The heterocyclic ring may be attached at any heteroatom or carbon atom provided the resultant structure is chemically stable. Such heterocyclic groups include, for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.
The term xe2x80x9csubstituted heterocyclicxe2x80x9d is used herein to describe the heterocyclic just defined having one to four substituents selected from the group which includes halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. The term xe2x80x9calkoxyxe2x80x9d is used herein to refer to the OR group, where R is alkyl or substituted alkyl. The term xe2x80x9caryloxyxe2x80x9d is used herein to refer to the OR group, where R is aryl or substituted aryl. The term xe2x80x9calkylcarbonylxe2x80x9d is used herein to refer to the RCO group, where R is alkyl or substituted alkyl. The term xe2x80x9calkylcarboxyxe2x80x9d is used herein to refer to the COOR group, where R is alkyl or substituted alkyl. The term xe2x80x9caminoalkylxe2x80x9d refers to both secondary and tertiary amines wherein the alkyl or substituted alkyl groups containing one to eight carbon atoms, which may be either same or different and the point of attachment is on the nitrogen atom xe2x80x9cHalogenxe2x80x9d refers to Cl, Br, F, or I.
The antiprogestin compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional xe2x80x9cpro-drugxe2x80x9d forms, which, when administered in such form, convert to the active moiety in vivo.
These methods may be used for contraception or treatment and/or prevention of secondary amenorrhea, dysfunctional bleeding, uterine leiomyomata, endometriosis; polycystic ovary syndrome, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, or minimization of side effects or cyclic menstrual bleeding. Additional uses of the invention include stimulation of food intake.
When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
These active agents of the methods and regimens herein may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringe ability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.
The antiprogestin compounds of this invention can be prepared following the Schemes illustrated below:
As demonstrated in Scheme I, the antiprogestin compounds of this invention are generally prepared by employing the suitable coupling reaction as a final step. An appropriately substituted ortho-amino acid or its derivatives such as ethyl ester (X=Br, I, Cl, or a latent coupling precursor such as alkoxy group which can be converted into OTf group suitable in the coupling reaction) is treated with a suitable organo metallic reagent, e.g. Grignard reagent, in appropriate nonprotic solvents which include but are not limited to THF or ether to give ortho-amino carbinol 2 under an inert atmosphere such as argon or nitrogen at xe2x88x9278xc2x0 C. to room temperature. Ring closure of carbinol 2 to yield oxazin-2-ones 3 is commonly effected by a condensing agent such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65xc2x0 C. The arylation of oxazin-2-ones 3 to yield 4 can be effected by various coupling reactions including Suzuki, Stille reactions etc. These reactions are commonly performed in the presence of transition metallic catalyst, e.g., palladium or nickel complex often with phosphino ligands, e.g., Ph3P, 1,1xe2x80x2-bis(diphenylphosphino)ferrocene, 1,2-bis(diphenylphosphino)ethane or palladium salts such as palladium acetate. Under this catalytic condition, an appropriately substituted nucleophilic reagent, e.g., aryl boronic acid, arylstannane, or aryl zinc compound, is coupled with oxazinones 3 to give compounds 4. If a base is needed in the reaction, the commonly used bases include but not limited to sodium bicarbonate, sodium carbonate, potassium phosphate, barium carbonate, potassium acetate, or cesium fluoride. The most commonly used solvents in these reactions include benzene, DMF, isopropanol, ethanol, DME, ether, acetone or a mixture of any one of these solvent and water. The coupling reaction is generally executed under an inert atmosphere such as nitrogen or argon at temperatures ranging from room temperature to 95xc2x0 C. Oxazinones 3 can be converted into a nucleophile such as boronic acid which can be coupled with an appropriate electrophile, e.g., aryl bromide or aryl iodide, to yield 6 employing the coupling reaction condition as described above. 
The transformation of 3 to 5 can be effected by treating 3 with an organo metallic reagent, e.g., n-BuLi, in a nonprotic solvent such as THF or ether followed by quenching the reaction solution wiht a suitable electrophile such as trimethil borate, triisopropyl borate, bishexalkyl tin reagent, or zinc chloride at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature under an inert atmosphere such as argon or nitrogen. Conversion of carbamate 6 to thiocarbamate 7 can be readily effeted by treatment of 6 with a suitable sulfur reagent such as P2S5 or Lawesson""s reagent in a suitable non-protic solvent such as toluene, chlorobenzene, benzene, or xylene under an inert atmosphere such as argon or nitrogen at the temperature of boiling solvent.
Scheme II describes the procedures to prepare oxazinones bearing two different substituents at position-4. The Weinreb amide 9 can be prepared from an appropriately substituted isatoic anhydride when treated with N-,O-dimethylhydroxyl-amine hydrochloride salt in a protic solvent such as ethanol or isopropanol at reflux under an inert atmosphere such as argon or nitrogen. Coupling of amide 9 with an aryl electrophile such as aryl boronic acid or arylstannane to give 10 can be effected by employing a typical coupling reaction such as Suzuki, Stille coupling procedure in a similar fashion as described for the preparation of oxazinones 4. Treatment of Weinreb amide 10 with organo metallic compounds, e.g., alkyllithium, alkynyllithium, aryllithium, or their Grignard counterpart in a nonprotic solvent such as TBF or ether under an inert atmosphere such as argon or nitrogen at xe2x88x9278xc2x0 C. to room temperature affords amino ketone 11. Conversion of ketone 11 to carbinol 12 can be effected by treatment of 10 with an organo metallic reagent such as alkyl, alkynyl, or aryl Grignard compound in a nonprotic solvent such as THE or ether under an inert atmosphere such as argon or nitrogen at xe2x88x9278xc2x0 C. to room temperature. Conversion of ketone 11 to carbinol 12 can also be effected by reduction of the ketone group of 11 to the carbinol moiety of 12 using an appropriate reducing reagent such as lithium aluminum hydride, sodium borohydride in a suitable solvent such as THF, ether, or anhydrous alcohol under an inert atmosphere in the temperature ranging from 0xc2x0 C. to the boiling point of the solvent. Ring closure of carbinol 12 to produce the compounds of this invention, 13, can be accomplished with condensing agents such as carbonyldiimidazole, phosgene, dimethylcarbonate, or diethylcarbonate in a suitable nonprotic solvent such as THF at temperatures ranging from room temperature to 65xc2x0 C. Conversion of carbamate 13 to thiocarbamate 14 can be readily effected by treatment of 13 with a suitable sulfur reagent such as P2S5 or Lawesson""s reagent in a suitable nonprotic solvent such as toluene, chlorobenzene, benzene, or xylene under an inert atmosphere such as argon or nitrogen at the temperature of boiling solvent. 
Alternatively, ortho-amino ketone 11 can be prepared by treatment of ortho-amino nitrile 16 with an organo metallic compound such as organo lithium reagent or Gringard reagent in a suitable solvent such as THF or ether under an inert atmosphere such as argon or nitrogen at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature as illustrated in Scheme III. Nitrile 16 can be readily prepared from an appropriately substituted nitrite such as bromobenzonitrile 15 using a suitable coupling reaction such as Stille or Suzuki protocol carried out in a similar fashion as described for the preparation of the Weinreb amide 10. 